For 35 years, this grant has supported studies involving the treatment of allergic diseases. For the last 25 of these, our focus has been on insect allergy. In 1976, we showed that the then standard treatment immunotherapy, with whole body extract, was no different than placebo, whereas treatment with venoms eliminated the reaction to sting. Venom immunotherapy rapidly became standard. Guidelines call for all history positive, skin test positive patients to receive venom immunotherapy, but this involves fully 3% of all United States citizens. European workers reported, about 8 years ago, that fully 75% of vespid allergic individuals with positive skin tests would not react to sting. We have confirmed that work. Our present goals build on the fact that we have very recently, developed laboratory tests which predict 98% of those patients who will not react. We would like to continue that work to develop laboratory tests, which identify who will react on sting. We are limited by the low reaction rate and so have joined forces with a colleague in rural Pennsylvania to obtain additional patients. We will also try to more closely approximate the field sting which usually takes place when patients are exercising. Even better, we will try to see if we can mimic a sting using very high concentrations of venom together with the vasodialators which are in venoms, such as histamine and kinins. We have recently found that the current diagnostic methods, that is the venom skin test and RAST, are not adequate. History positive, skin test positive and negative patients have the same rate of reactions to sting. We will tempt to improve the skin test material by dialysis and/or working with the purified major allergen of yellow jackets, Ves v 5. We hope to extend our studies into large local reactions, which occur 3-5 times more commonly than systemic reactions. In about one-third of such patients, the reactions are sufficiently painful to require medication with steroids. We intend to demonstrate that immunotherapy will ablate this type of reaction. Finally, we are collaborating with a company, Dynavax Technologies Corporation*, which has shown that allergens linked to bacterial oligonucleotides containing the CpG mot have decreased allergenicity and changed a Th2- to a Th1-like response. Since there is a 50% systemic reaction rate ring venom immunotherapy, we would like less harmful and more effective materials for immunotherapy. Finally, our most recent studies have shown that not all patients can discontinue venom immunotherapy after 5 years, which is the current recommendation, and that not all children outgrow insect allergy. We need to continue to study these patients to develop the most useful clinical guidelines.